Adenoviral Transfer of Rho Family Proteins to Lung Cancer Cells Ameliorates Cell Proliferation and Motility and Increases Apoptotic Change

Lung cancer is still a very severe disease which has a low survival rate due to localinvasion and metastasis potentials in spite of many clinical challenges using anti-cancerdrugs. Rho family small GTPases play pivotal roles in cell invasion and metastasisduring carcinogenesis. In this study, we explored the inhibitory effect of adenoviralvector encoding dominant negative mutants of Rac, RhoA, and ROCK in humannon-small cell lung carcinoma cell lines (A549 and SQ5) and mouse carcinoma cell line(Lewis lung carcinoma, LLC). These cells showed high expression of Rac, Rho, andROCK, whereas only faint bands were detected in normal human lung epithelial cells,BET-1A. The efficiency of adenoviral vector transfer was stronger in A549 and SQ5cells than LLC cells. Dominant negative forms of RhoA (Rho-DN) and Rac (Rac-DN)decreased cell proliferation in WST-8 assay and increased the number of apoptotic cellsin both A549 and SQ5 cells by Hoechst 33258 and TUNEL staining. On the otherhand, DN form of ROCK (ROCK-DN) did not show any apparent changes comparedwith the other proteins. Transwell○!R chamber analysis showed that migration/invasionactivity was significantly suppressed by gene transfection both in A549 and SQ5 cellsand that ROCK-DN gene transfer required a higher multiplicity of infection to showeffects similar to Rho and Rac. Although the effect of gene therapy is cell-dependent,these data suggest that adenoviral gene transfer with Rho family small GTPases is onegood approach to lung cancer therapy

Randomized Phase II Study of Two Different Schedules of Gemcitabine and Oral S-1 in Chemo-naïve Patients with Advanced Non-small Cell Lung Cancer

IntroductionThis study was conducted to evaluate the efficacy and safety and to compare dosing schedules of gemcitabine combined with S-1 in chemo-naïve non-small cell lung cancer patients.MethodsPatients with chemo-naïve stage IIIB/IV non-small cell lung cancer were randomized into two treatment arms. Patients were given oral S-1 (60 mg/m2/d, twice a day) from days 1 to 14 with gemcitabine (1000 mg/m2/d) on days 1 and 8 (arm A) or on days 8 and 15 (arm B). This cycle was repeated every 21 days.ResultsA total of 80 patients were entered in this trial. The primary end point of this study was response rate. The response rates of arm A and arm B were 22.0 and 28.9%, respectively (p = 0.606). Median time to treatment failure in arm A was 3.6 months and 4.8 months in arm B. Median time to progression in arm A was 4.1 months and 5.5 months in arm B. Median survival time in arm A and arm B was 15.5 months and 18.8 months, respectively. The toxicity profile was relatively mild and did not differ very much between two arms.ConclusionThe combination of gemcitabine and S-1 was determined to be feasible and effective for advanced non-small cell lung cancer. We selected arm B for further studies because of its higher response rate and survival data